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However, the underlying mechanisms remain unclear. In this study, we investigated the role of EMPA in alleviating hepatic steatosis through the modulation of O\u2010GlcNAcylation. High\u2010glucose (HG)\u2013induced alpha mouse liver 12 (AML12) cells, mouse primary hepatocytes (MPHs), and murine MASLD models (high\u2010fat diet\u2013fed and ob\/ob mice) were used to examine the effects of EMPA. Protein O\u2010GlcNAcylation, lipid accumulation, and AMP\u2010activated protein kinase \u03b1 (AMPK\u03b1) regulation were evaluated using Western blotting, immunostaining, and siRNA knockdown. Our findings showed that protein O\u2010GlcNAcylation levels were elevated in both in\u00a0vitro and in\u00a0vivo models. EMPA treatment reduced O\u2010GlcNAcylation and ameliorated lipid accumulation in HG\u2010induced AML12 cells, MPHs, and MASLD models. Knockdown of O\u2010GlcNAc transferase (OGT) decreased O\u2010GlcNAcylation levels and lipid accumulation in HG\u2010induced AML12 cells. Additionally, OGT knockdown altered both O\u2010GlcNAcylated and phosphorylated AMPK\u03b1 levels. In these models, EMPA administration decreased O\u2010GlcNAcylated AMPK\u03b1 while increasing phosphorylated AMPK\u03b1. This study further identified serine 344, threonine 447, and serine 501 as critical O\u2010GlcNAcylation sites on AMPK\u03b12. Mutation of these residues to alanine in AMPK\u03b12 attenuated lipid accumulation in AML12 cells, with no additional improvement observed following EMPA treatment. In summary, EMPA effectively improves hepatic steatosis by modulating the O\u2010GlcNAcylation states of AMPK\u03b1. Identification of specific O\u2010GlcNAcylation sites on AMPK\u03b12 highlights their importance in the therapeutic mechanism of EMPA in improving hepatic steatosis.<\/jats:p>","DOI":"10.1096\/fj.202500538rr","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T09:30:13Z","timestamp":1761125413000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Empagliflozin Downregulates AMP\u2010Activated Protein Kinase\u03b1 O\u2010GlcNAcylation to Ameliorate Hepatic Steatosis"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-7000","authenticated-orcid":false,"given":"Yicheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang China"},{"name":"Department of Endocrinology and Metabolic Diseases The Eighth Affiliated 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